Deciphering the function of granule cell interneurons in the mouse main olfactory bulb: Insights from adult neurogenesis and local-field potentials

Abstract

The olfactory bulb is the first olfactory circuit where information doesn't make sense. This circuit takes genetically ordered inputs and scrambles them into outputs that, despite decades of research, have not been decoded. Olfactory bulb output is greatly shaped by interactions between granule cell interneurons and mitral/tufted cell principal neurons. Granule cell interneurons are particularly interesting because they are continuously replaced during adulthood and because their connectivity indicates that they integrate disparate inputs from higher brain regions. However, it is unclear how these unique features impact circuit function. This thesis examines the function of granule cells by manipulating their adult neurogenesis and by probing circuit function after genetic manipulation. We present five general findings. 1) The structure and the function of the granule cell layer is resistant to changes in the magnitude of adult neurogenesis. 2) Animals with reduced adult neurogenesis have behavioral disruptions to a larger system that includes cortical and limbic regions in the association between odors and fear. By probing the synapse between granule and mitral cells we found that: 3) the granule-mitral cell circuit functions with spatial homogeneity indicating distributed synaptic connectivity. 4) Granule cells are modulated by the breathing rate of the animal, and disruptions to this modulation in prion protein knockout mice are associated with the inability to make olfactory discriminations. Finally: 5) evidence from AC3-/- anosmic mice suggests that centrifugal inputs impose a centrally generated breathing rhythm onto granule cells. These results generally support a model where granule cells function by focusing temporal patterns of centrifugal input onto distributed ensembles of mitral cells